Targeting histone deacetylases for the treatment of immune, endocrine and metabolic disorders

The 'histone code' is a well-established hypothesis describing the idea that specific patterns of post-translational modifications to histones act like a molecular "code" recognised and used by non-histone proteins to regulate specific chromatin functions. One modification which has received significant attention is that of histone acetylation. The enzymes which regulate this modification are described as histone acetyltransferases or HATs, and histone deacetylases or HDACs. Due to their conserved catalytic domain HDACs have been actively targeted as a therapeutic target. The proinflammatory environment is increasingly being recognised as a critical element for both degenerative diseases and cancer. The present review will discuss the current knowledge surrounding the clinical potential & current development of histone deacetylases for the treatment of diseases for which a proinflammatory environment plays important roles, and the molecular mechanisms by which such inhibitors may play important functions in modulating the proinflammatory environment. © 2009 Bentham Science Publishers Ltd.

Time course-dependent changes in the transcriptome of human skeletal muscle during recovery from endurance exercise: From inflammation to adaptive remodeling

Re-programming of gene expression is fundamental for skeletal muscle adaptations in response to endurance exercise. This study investigated the time-course dependent changes in the muscular transcriptome following an endurance exercise trial consisting of 1 h of intense cycling immediately followed by 1 h of intense running. Skeletal muscle samples were taken at baseline, 3 h, 48 h, and 96 h post-exercise from eight healthy, endurance-trained, male individuals. RNA was extracted from muscle. Differential gene expression was evaluated using Illumina microarrays and validated with qPCR. Gene set enrichment analysis identified enriched molecular signatures chosen from the Molecular Signatures Database. Three h post-exercise, 102 gene sets were up-regulated [family wise error rate (FWER), P < 0.05]; including groups of genes related with leukocyte migration, immune and chaperone activation, and cyclic AMP responsive element binding protein (CREB) 1-signaling. Forty-eight h post-exercise, among 19 enriched gene sets (FWER, P < 0.05), two gene sets related to actin cytoskeleton remodeling were up-regulated. Ninety-six h post-exercise, 83 gene sets were enriched (FWER, P < 0.05), 80 of which were up-regulated; including gene groups related to chemokine signaling, cell stress management, and extracellular matrix remodeling. These data provide comprehensive insights into the molecular pathways involved in acute stress, recovery, and adaptive muscular responses to endurance exercise. The novel 96 h post-exercise transcriptome indicates substantial transcriptional activity, potentially associated with the prolonged presence of leukocytes in the muscles. This suggests that muscular recovery, from a transcriptional perspective, is incomplete 96 h after endurance exercise involving muscle damage.

Impact of cognitive behaviour therapy via mail for cessation of benzodiazepine use : a series of case reports

Benzodiazepines are widely prescribed to manage sleep disorders, anxiety and muscular tension. While providing short-term relief, continued use induces tolerance and withdrawal, and in older users, increases the risk of falls. However, long-term prescription remains common, and effective interventions are not widely available. This study developed a self-managed cognitive behaviour therapy package for cessation of benzodiazepine use delivered to participants via mail (M-CBT) and trialled its effectiveness as an adjunct to a general practitioner (GP)-managed dose reduction schedule. In the pilot trial, participants were randomly assigned to GP management with immediate or delayed M-CBT. Significant recruitment and engagement problems were experienced, and only three participants were allocated to each condition. After immediate M-CBT, two participants ceased use, while none receiving delayed treatment reduced daily intake by more than 50%. Across the sample, doses at 12 months remained significantly lower than baseline, and qualitative feedback from participants was positive. While M-CBT may have promise, improved engagement of GPs and participants is needed for this approach to substantially impact on community-wide benzodiazepine use.

The Habitual Rhythms of Becoming-Involved: Insights into Participation Experiences in Urban Spaces by Children with Diverse Mobility

This chapter reports on a study that reveals the essence of participation in urban spaces by ten children who live with various physical conditions: Muscular Dystrophy, Cerebral Palsy, and Autoimmune Rheumatic Diseases. These conditions affect muscle and movement differently resulting in diverse ways in which children move through space (personal mobility). The children at the time of the research were 9-12 years of age residing in South-east Queensland, Australia. The approach and methods selected for this study, interpretive phenomenological inquiry and grounded theory, were chosen for their capacity to capture the complexity and multiple interactions of the child’s urban living. The confronting and poignant accounts by children and their families of their experiences produced a new way of understanding the concept of participation, as a ‘journey of becoming involved.’ Their accounts of performing everyday routines (e.g. leaving home, getting in and out of the car, and entering places) in urban spaces (neighbourhood streets, schools, open spaces, shopping centres, and hospitals) revealed differences in the way settings were experienced. These differences were associated with the interplay between the body, space and context. Where interplays were problematic, explicit decisions about children’s involvement were made. These decisions were described in terms of ‘avoid going’, ‘pick and choose’, ‘discontinue’, ‘accept’, or ‘contest.’ What these decisions mean is some spaces are avoided, some journeys are discontinued, and some barriers encountered in journeys are normalised as everyday experiences, i.e. ‘tolerable discrimination’. These actions resulted in experiences of non-participation or partial–tokenistic participation. The key substantive contribution of the research lies in the identification of points in children’s journeys that shape participation experience. These points identify where future interventions in policy, programming and design can be made to make real and sustaining changes to lives of children and their families in geographies crucial to urban living.

The Journey of Becoming Involved in Urban Spaces by Children with Diverse Mobility

Participation is a word frequently espoused in the literature of childhood and urban studies. It has also been made sacrosanct through the Convention on the Rights of the Child and other rights-based policy and programming. Despite this importance, what it means and how it is experienced in the everyday lives of children with diverse abilities is not well understood. This chapter provides insight into the everyday experiences of participation by ten children 9-12 years of age, who have diverse personal mobility from various physical conditions that affect muscle and movement differently, including: Muscular Dystrophy, Cerebral Palsy, and Autoimmune Rheumatic Diseases. The children participants live in the outer suburbs and inner regions of south-east Queensland, Australia. The chapter discusses a new way of understanding and theorising participation as a journey of becoming involved. This knowledge emerged through the children’s body-space-time routines (body ballets) and their descriptions of inhabiting urban space. This chapter also establishes how body-space-context interplays shape the experiences of becoming and being involved in everyday life, as well as the preconceptions of body embed in space which divide and constrain children and families actualisation of full and genuine participation.

A biomechanical study of spherical grip

Use of the hand is vital in working life due to the grabbing and pinching it performs. Spherical grip is the most commonly used, due to similarity to the gripping of a computer mouse. Knowledge of its execution and the involved elements is essential. Analysis of this exertion with surface electromyography devices (to register muscular activity) and accelerometer devices (to register movement values ) can provide multiple variables. Six subjects performed ball gripping and registered real-time electromyography (thenar region, hypothenar region, first dorsal interosseous, flexors of the wrist, flexor carpi ulnaris and extensors of the wrist muscles) and accelerometer (thumb, index, middle, ring, pinky and palm) values. The obtained data was resampled “R software” and processed “Matlab Script” based on an automatic numerical sequence recognition program. Electromyography values were normalized on the basis of maximum voluntary contraction, whilst modular values were calculated for the acceleration vector. After processing and analysing the obtained data and signal, it was possible to identify five stages of movement in accordance with the module vector from the palm. The statistical analysis of the variables was descriptive: average and standard deviations. The outcome variables focus on the variations of the modules of the vector (between the maximum and minimum values of each module and phase) and the maximum values of the standardized electromyography of each muscle. Analysis of movement through accelerometer and electromyography variables can give us an insight into the operation of spherical grip. The protocol and treatment data can be used as a system to complement existing assessments in the hand.

Statistical methods for electromyography data and associated problems

This thesis proposes three novel models which extend the statistical methodology for motor unit number estimation, a clinical neurology technique. Motor unit number estimation is important in the treatment of degenerative muscular diseases and, potentially, spinal injury. Additionally, a recent and untested statistic to enable statistical model choice is found to be a practical alternative for larger datasets. The existing methods for dose finding in dual-agent clinical trials are found to be suitable only for designs of modest dimensions. The model choice case-study is the first of its kind containing interesting results using so-called unit information prior distributions.

An exercise intervention during chemotherapy for women with recurrent ovarian cancer: A feasibility study

Objective: The aim of this study was to determine the feasibility of a combined supervised and home-based exercise intervention during chemotherapy for women with recurrent ovarian cancer. Secondary aims were to determine the impact of physical activity on physical and psychological outcomes and on chemotherapy completion rates. Methods: Women with recurrent ovarian cancer were recruited from 3 oncology outpatient clinics in Sydney and Canberra, Australia. All participants received an individualized exercise program that consisted of 90 minutes or more of low to moderate aerobic, resistance, core stability, and balance exercise per week, for 12 weeks. Feasibility was determined by recruitment rate, retention rate, intervention adherence, and adverse events. Aerobic capacity, muscular strength, fatigue, sleep quality, quality of life, depression, and chemotherapy completion rates were assessed at weeks 0, 12, and 24. Results: Thirty participants were recruited (recruitment rate, 63%), with a retention rate of 70%. Participants averaged 196 ± 138 min · wk of low to moderate physical activity throughout the intervention, with adherence to the program at 81%. There were no adverse events resulting from the exercise intervention. Participants who completed the study displayed significant improvements in quality of life (P = 0.017), fatigue (P = 0.004), mental health (P = 0.007), muscular strength (P = 0.001), and balance (P = 0.003) after the intervention. Participants completing the intervention had a higher relative dose intensity than noncompleters (P = 0.03). Conclusions: A program consisting of low to moderate exercise of 90 min · wk was achieved by two-thirds of women with recurrent ovarian cancer in this study, with no adverse events reported. Randomized control studies are required to confirm the benefits of exercise reported in this study.

Electromyography and sonomyography analysis of the tibialis anterior: a cross sectional study

Background Foot dorsiflexion plays an essential role in both controlling balance and human gait. Electromyography (EMG) and sonomyography (SMG) can provide information on several aspects of muscle function. The aim was to establish the relationship between the EMG and SMG variables during isotonic contractions of foot dorsiflexors. Methods Twenty-seven healthy young adults performed the foot dorsiflexion test on a device designed ad hoc. EMG variables were maximum peak and area under the curve. Muscular architecture variables were muscle thickness and pennation angle. Descriptive statistical analysis, inferential analysis and a multivariate linear regression model were carried out. The confidence level was established with a statistically significant p-value of less than 0.05. Results The correlation between EMG variables and SMG variables was r = 0.462 (p < 0.05). The linear regression model to the dependent variable “peak normalized tibialis anterior (TA)” from the independent variables “pennation angle and thickness”, was significant (p = 0.002) with an explained variance of R2 = 0.693 and SEE = 0.16. Conclusions There is a significant relationship and degree of contribution between EMG and SMG variables during isotonic contractions of the TA muscle. Our results suggest that EMG and SMG can be feasible tools for monitoring and assessment of foot dorsiflexors. TA muscle parameterization and assessment is relevant in order to know that increased strength accelerates the recovery of lower limb injuries.

Monitoring changes of the tibialis anterior during dorsiflexion with electromyography, sonomyography, dynamometry and kinematic signals

Dorsiflexion (DF) of the foot plays an essential role in both controlling balance and human gait. Electromyography and Sonomyography can provide information on several aspects of muscle function. The aim was to describe a new method for real-time monitoring of muscular activity, as measured using EMG, muscular architecture, as measured using SMG, force, as measured using dynamometry, and kinematic parameters, as measured using IS during isometric and isotonic contractions of the foot DF. The present methodology may be clinically relevant because it involves a reproducible procedure which allows the function and structure of the foot DF to be monitored.

An exploratory ergonomic study of musculoskeletal disorder prevention in the Queensland Ambulance Service

From 2008-09 to 2012-13, the most prevalent worker compensation claim in the Queensland Ambulance Service (QAS) was musculoskeletal injuries at >80%. This is consistent with literature that shows Musculoskeletal Disorders (MSD) was one of the front runners for workplace injuries among many professions. In an attempt to reduce the injury rate and related claims, the QAS created a selection criterion for their workers based on the Health Related Fitness Test. This method intended to select workers based upon their fitness level, instead of selecting for their ability to perform the tasks or modify the tasks to better suit the workers. With injury rates remaining high, further research produced the Patient Handling Equipment Project Report, which provided the background for the Manual Handling Program Book. The Manual Handling Program Book however lacks in accurately addressing musculoskeletal hazards; actions which cause or avoid injury, correct posture and motion for patient movement, muscular biomechanics, static and dynamic workload including activities causing strain, and equipment use in relation to musculoskeletal hazards. The exploratory research aims to better understand the ambulance service’s perception of Manual Materials Handling (MMH), how it relates to musculoskeletal injuries and how the service has attempted to reduce its prevalence. Based on a literature review and a critical analysis of the QAS Health Related Fitness Test, QAS Patient Handling Equipment Project Report and the QAS Manual Handling Program Book, an understanding of their shortfalls in the prevention of musculoskeletal injuries was gained. This entails understanding the work tasks, workloads, strains and workflow of paramedics. This research creates a starting point for further research into musculoskeletal injuries in paramedics. This study specifically looks at hazards related to musculoskeletal disorders. It identifies work system deficiencies that contribute to the prevalence of musculoskeletal injuries, and possible interventions to avoid them in paramedics.

Study on tracheal collapsibility, compliance, and stress by considering nonlinear mechanical property of cartilage

Tracheal cartilage has been widely regarded as a linear elastic material either in experimental studies or in analytic and numerical models. However, it has been recently demonstrated that, like other fiber-oriented biological tissues, tracheal cartilage is a nonlinear material, which displays higher strength in compression than in extension. Considering the nonlinearity requires a more complex theoretical frame work and costs more to simulate. This study aims to quantify the deviation due to the simplified treatment of the tracheal cartilage as a linear material. It also evaluates the improved accuracy gained by considering the nonlinearity. Pig tracheal rings were used to exam the mechanical properties of cartilage and muscular membrane. By taking into account the asymmetric shape of tracheal cartilage, the collapse behavior of complete rings was simulated, and the compliance of airway and stress in the muscular membrane were discussed. The results obtained were compared with those assuming linear mechanical properties. The following results were found: (1) Models based on both types of material properties give a small difference in representing collapse behavior; (2) regarding compliance, the relative difference is big, ranging from 10 to 40% under negative pressure conditions; and (3) the difference in determining stress in the muscular membrane is small too: <5%. In conclusion, treating tracheal cartilage as a linear material will not cause big deviations in representing the collapse behavior, and mechanical stress in the muscular part, but it will induce a big deviation in predicting the compliance, particularly when the transmural pressure is lower than -0.5 kPa. The results obtained in this study may be useful in both understanding the collapse behavior of trachea and in evaluating the error induced by the simplification of treating the tracheal cartilage as a linear elastic material.

Study of tracheal collapsibility, compliance and stress by considering its asymmetric geometry

The shape of tracheal cartilage has been widely treated as symmetric in analytical and numerical models. However, according to both histological images and in vivo medical image, tracheal cartilage is of highly asymmetric shape. Taking the cartilage as symmetric structure will induce bias in calculation of the collapse behavior, as well as compliance and muscular stress. However, this has been rarely discussed. In this paper, tracheal collapse is represented by considering its asymmetric shape. For comparison, the symmetric shape, which is reconstructed by half of the cartilage, is also presented. A comparison of cross-sectional area, compliance of airway and stress in the muscular membrane, determined by asymmetric shape and symmetric shape is made. The result indicates that the symmetric assumption brings a small error, around 5% in predicting the cross-sectional area under loading conditions. The relative error of compliance is more than 10%. Particularly when the pressure is close to zero, the error could be more than 50%. The model considering the symmetric shape results in a significant difference in predicting stress in muscular membrane by either under- or over-estimating it. In conclusion, tracheal cartilage should not be treated as a symmetric structure. The results obtained in this study are helpful in evaluating the error induced by the assumption in geometry.

Exercise and psychosocial interventions in breast cancer survivors: Preliminary results of a randomized controlled trial

Physical and psychological decline is common in the post-treatment breast cancer population, yet the efficacy of concurrent interventions to meet both physical- psychosocial needs in this population has not been extensively examined. PURPOSE: This study explores the effects of a combined exercise and psychosocial intervention model on selected physiological-psychological parameters in post-treated breast cancer. METHODS: Forty-one breast cancer survivors were randomly assigned to one of four groups for an 8-week intervention: exercise only [EX, n=13] (aerobic and resistance training), psychosocial therapy only [PS, n=11] (biofeedback), combined EX and PS [EX+PS, n=11], or to control conditions [CO, n=6]. Mean delta score (post-intervention - baseline) were calculated for each of the following: body weight, % body fat (skin folds), predicted VO2max (Modified Bruce Protocol), overall dynamic muscular endurance [OME] (RMCRI protocol), static balance (Single leg stance test), dynamic balance (360° turn and 4-square step test), fatigue (Revised Piper Scale), and quality of life (FACT-B). A one-way ANOVA was used to analyze the preliminary results of this on-going randomized trial. RESULTS: Overall, there were significant differences in the delta scores for predicted VO2max, OME, and dynamic balance among the 4 groups (p<0.05). The EX+PS group showed a significant improvement in VO2max compared with the PS group (4.2 ± 3.8 vs. -0.9 ± 4.2 mL/kg/min; p<0.05). Both the EX+PS and EX groups showed significant improvements in OME compared with the PS and CO groups (44.5 ± 23.5 and 43.4 ± 22.1 vs. -3.9 ± 15.2 and 2.7 ± 13.7 repetitions; p<0.05). All 3 intervention groups showed significant improvements in dynamic balance compared with the CO group (-0.8 ± 0.6, -0.6 ± 0.8, and -0.6 ±1.0 vs. 0.6 ± 0.6 seconds; p<0.05). Overall, changes in fatigue tended towards significance among the 4 groups (p = 0.08), with decreased fatigue in the intervention groups and increased fatigue in the CO group. CONCLUSIONS: Our preliminary findings suggest that EX and PS seem to produce greater positive changes in the outcome measures than CO. However, at this point no definite conclusions can be made on the additive effects of combining the EX and PS interventions.

Genetics of heifer performance in 'wet' and 'dry' seasons and their relationships with steer performance in two tropical beef genotypes.

The genetics of heifer performance in tropical 'wet' and 'dry' seasons, and relationships with steer performance, were studied in Brahman (BRAH) and Tropical Composite (TCOMP) (50% Bos indicus, African Sanga or other tropically adapted Bos taurus; 50% non-tropically adapted Bos taurus) cattle of northern Australia. Data were from 2159 heifers (1027 BRAH, 1132 TCOMP), representing 54 BRAH and 51 TCOMP sires. Heifers were assessed after post-weaning 'wet' (ENDWET) and 'dry' (ENDDRY) seasons. Steers were assessed post-weaning, at feedlot entry, over a 70-day feed test, and after similar to 120-day finishing. Measures studied in both heifers and steers were liveweight (LWT), scanned rump fat, rib fat and M. longissimus area (SEMA), body condition score (CS), hip height (HH), serum insulin-like growth factor-I concentration (IGF-I), and average daily gains (ADG). Additional steer measures were scanned intra-muscular fat%, flight time, and daily (DFI) and residual feed intake (RFI). Uni- and bivariate analyses were conducted for combined genotypes and for individual genotypes. Genotype means were predicted for a subset of data involving 34 BRAH and 26 TCOMP sires. A meta-analysis of genetic correlation estimates examined how these were related to the difference between measurement environments for specific traits. There were genotype differences at the level of means, variances and genetic correlations. BRAH heifers were significantly (P < 0.05) faster-growing in the 'wet' season, slower-growing in the 'dry' season, lighter at ENDDRY, and taller and fatter with greater CS and IGF-I at both ENDWET and ENDDRY. Heritabilities were generally in the 20 to 60% range for both genotypes. Phenotypic and genetic variances, and genetic correlations, were commonly lower for BRAH. Differences were often explained by the long period of tropical adaptation of B. indicus. Genetic correlations were high between corresponding measures at ENDWET and ENDDRY, positive between fat and muscle measures in TCOMP but negative in BRAH (mean of 13 estimates 0.50 and -0.19, respectively), and approximately zero between steer feedlot ADG and heifer ADG in BRAH. Numerous genetic correlations between heifers and steers differed substantially from unity, especially in BRAH, suggesting there may be scope to select differently in the sexes where that would aid the differing roles of heifers and steers in production. Genetic correlations declined as measurement environments became more different, the rates of decline (environment sensitivity) sometimes differing with genotype. Similar measures (LWT, HH and ADG; IGF-I at ENDWET in TCOMP) were genetically correlated with steer DFI in heifers as in steers. Heifer SEMA was genetically correlated with steer feedlot RFI in BRAH (0.75 +/- 0.27 at ENDWET, 0.66 +/- 0.24 at ENDDRY). Selection to reduce steer RFI would reduce SEMA in BRAH heifers but otherwise have only small effects on heifers before their first joining.